PROJECT SUMMARY Mn is an essential metal with neurotoxic properties in excess. Increasingly high exposure to manganese (Mn) in adults is associated with subclinical parkinsonian movements and postural instability, increased risk for Parkinson's disease (PD) or parkinsonism, and at the highest levels with manganism, a parkinsonian-like disorder, which is not ameliorated after cessation of exposure. Developmental and childhood Mn exposures have been associated with cognitive, behavioral as well as motor function alterations. Mn neurotoxicity involves both direct toxicity to neurons as well as neuroinflammatory responses. Here, we propose to continue our Mn neurotoxicity research program with a focus on the identification and mechanistic relationships of precise molecular targets of Mn neurotoxicity with exposures proximate to the transition from replete to neurotoxic levels of Mn ? environmentally relevant dosing. We hypothesize that threshold-level Mn neurotoxicity occurs via alteration of Mn-dependent/-activated biological functions. We will test the hypothesis as follows: In Specific Aim 1 we will identify the mechanistic basis by which Mn alters insulin/insulin-like growth factor (IGF) related metabolic pathway signaling in neurons and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems, both in worms and mammalian systems. Studies in Specific Aim 2 will refute or establish a mechanistic relationship between dopamine (DA) neurobiology and the insulin/IGF related signaling pathways in Mn neurotoxicity. Finally, in Specific Aim 3, we will define the mechanistic relationships of the insulin/IGF related signaling pathways and cellular Mn neurotoxicity outcomes. This highly interactive experimental design brings to bear innovative and complementary expertise to assess functional domains that regulate key nodes of interaction between Mn and biological systems, focusing on whether the threshold-level for Mn-induced neurotoxicity occurs via alteration of Mn-dependent/-activated biological functions. The studies are geared to address these timely objectives with translational extrapolation from the nematode to humans.